Cadmium is a heavy metal that occurs naturally in the environment. In addition to the natural levels in soil, increased application of phosphate fertilizers and sewage sludge to cropland beginning in the latter half of the late 20th century resulted in increased cadmium in foodstuffs and tobacco, earning it notoriety as the Trojan horse of the green revolution. Historically, cadmium-health research has focused on health effects from high exposures occurring in small subpopulations. However, epidemiologic and mechanistic evidence accumulated during the past decade suggests widespread health risks from low-level, chronic exposure to cadmium, including endocrine disruption and increased risk for breast and endometrial cancer along with reproductive effects, osteoporosis, renal function, cardiovascular disease and periodontal disease. Importantly, the early epidemiologic and mechanistic evidence suggests that increased risk may be observed at levels of exposure common to 30-60% of the population, which emphasizes the need for focused research on the effects of low-level cadmium. This competitive revision application proposes the creation of a cadmium consortium that builds onto the parent project: a prospective case-cohort epidemiologic study designed to test the hypothesis that cadmium contributes to the high incidence of breast cancer in Western populations. The proposed consortium will enhance the parent project while providing novel findings in its own right, findings that will guide future studies and clinical application of risk assessment for cadmium exposure. One aim will investigate temporal variability in urinary cadmium levels. This biomarker has the promise of being a rare long-term indicator of decades-long exposure; however, validation studies in lower-exposure populations, such as those in the U.S., are necessary to assess whether a single spot urine sample is a stable, reproducible estimate of cadmium body burden. A second aim will develop molecular biomarkers to help identify biological endpoints of exposure and possible connections to the carcinogenic process, considering interplay between cadmium, zinc, and metallothionein. A third aim will investigate DNA methylation profiles and their association with breast cancer and cadmium, making this one of the first prospective studies of epigenetic markers and cancer, and one of the first to examine cadmium's role in epigenetic processes in a human population. This new consortium will bridge population-level and molecular efforts to bring novel insights to the understanding of health risks from cadmium, using advances in exposure science, epigenetics, biochemical analysis, and biomarkers. Of note, there is great potential for disease prevention, with more extensive regulation to avoid population exposure, because primary sources of exposure to cadmium for the general population, e.g., fertilizer, are already well recognized.